Season 1 begins with the aftermath of a plane crash which leaves the surviving passengers of Oceanic Airlines Flight 815 on what seems to be an uninhabited tropical island. Jack Shephard, a doctor, becomes their de facto leader. Their survival is threatened by a number of mysterious entities, including polar bears, an unseen creature that roams the jungle (the "Smoke Monster"), and the island's malevolent inhabitants known as "The Others". They encounter a French woman named Danielle Rousseau who was shipwrecked on the island 16 years before the main story and is desperate for news of a daughter named Alex. They also find a mysterious metal hatch buried in the ground. While two survivors, Locke and Boone, try to force the hatch open, four others, Michael, Jin, Walt and Sawyer attempt to leave on a raft that they have built. Meanwhile, flashbacks centered on individual survivors detail their lives prior to the plane crash.

Season 2 follows the growing conflict between the survivors and the Others, and continues the theme of the clash between faith and science, while resolving old mysteries and posing new ones. The four survivors in the raft are ambushed by the Others, and they take Walt, Michael's son. The survivors are forced to return to the island, where they find the tail-section survivors (the "Tailies"). A power struggle between Jack and John Locke over control of the guns and medicine located in the hatch develops, resolved in "The Long Con" by Sawyer when he gains control of them. The hatch is revealed to be a research station built by the Dharma Initiative, a scientific research project that involved conducting experiments on the island decades earlier. A man named Desmond Hume had been living in the hatch for three years, pushing a button every 108 minutes to prevent a catastrophic event from occurring. To recover his son, Michael betrays the survivors and Jack, Sawyer and Kate are captured. Michael is given a boat and leaves the island with his son, while John destroys the computer in the hatch, and so an electromagnetic event shakes the island. This causes the island to be detected in the exterior world, and it is revealed that a similar event caused the break-up of the plane.

In Season 3, the crash survivors learn more about the Others and their long history on the mysterious island and the fate of the Dharma Initiative. The leader of the Others, Benjamin Linus, is introduced as well as defections from both sides pave the way for conflict between the two. Time travel elements also begin to appear in the series, as Desmond is forced to turn the fail-safe key in the hatch to stop the electromagnetic event, and this sends his mind eight years to the past. When he returns to the present, he is able to see the future. Kate and Sawyer escape the Others, while Jack stays after Ben promises that Jack will be able to leave the island in a submarine if he operates on Ben, who has cancer. Jack does, but the submarine is destroyed by John. Jack is left behind with Juliet, an Other, who also seeks to leave the island, while John joins the Others. A helicopter crashes near the island, in which Naomi arrives, who says her freighter, Kahana, is near, and was sent by Penelope Widmore, Desmond's ex-girlfriend. Desmond has a vision in which Charlie will drown after shutting down a signal which prevents communication with the exterior world. His vision comes true, but Charlie speaks with Penelope who says she doesn't know any Naomi. Before drowning, Charlie writes in his hand "Not Penny's Boat" so Desmond can read it. Meanwhile, the survivors make contact with a rescue team aboard the freighter. In the season's finale, apparent flashbacks show a depressed Jack going to somebody's funeral. In the final scene these are revealed to be "flash forwards", and Kate and Jack are revealed to have escaped the island. Jack, however, is desperate to go back.

Season 4 focuses on the survivors dealing with the arrival of people from the freighter, who have been sent to the island to reclaim it from Benjamin. "Flash forwards" continue, in which it is seen how six survivors live their lives after escaping the island, and are dubbed the "Oceanic Six". The "Oceanic Six" are Jack, Kate, Hurley, Sayid, Sun and Aaron. In the present, four members of the freighter arrive, and team up with the survivors to escape the island, since the people of the freighter have orders to kill everyone who stays. Meanwhile, Ben travels with John to see Jacob, the island's leader. John enters his house, but finds Jack's dead father, Christian, who says he can speak on Jacob's behalf, and orders John to "move" the island. Ben takes John to an underground station in which time travel was researched. John becomes the new leader of the Others, while Ben moves the island by turning a giant frozen wheel, after which he is transported to the Sahara Desert. The six survivors escape in a helicopter as they watch the island disappear, and are subsequently rescued by Penelope. In the season finale, it is revealed that the funeral Jack went to in the "flash forwards" was John Locke's, who had been seeking out the Oceanic Six in his efforts to convince them to return to the island.

Season 5 follows two timelines. The first takes place on the island where the survivors who were left behind erratically jump forward and backward through time. In one of these time periods, John speaks with Richard Alpert, one of the Others, who says that to save the island, he must bring everyone back. John goes to the same underground station Ben went to. After moving the wheel himself, John is transported to the Sahara Desert in 2007, as the time shifts on the island stop and the survivors are stranded with the Dharma Initiative in 1974. In 2007, John contacts the Oceanic Six but no one wants to return. The last one he finds is a depressed Jack. John tells Jack his father is alive on the island. This seriously affects Jack and he begins taking flights, hoping to crash on the island again. Ben finds John and kills him. After John's death, the Oceanic Six are told to board the Ajira Airways Flight 316 to return to the island, and to go back they have to take John Locke's body in the plane. They take the flight, but some land in 1977, in which they meet with the other survivors who are now part of the Dharma Initiative, and others land in 2007. The survivors in 1977 are told by Daniel Faraday that if they detonate a hydrogen bomb at the hatch's construction site, the electromagnetic energy below it will be negated, and thus the hatch would never be built, and thus their future could be changed. In 2007, John Locke apparently comes back to life. He instructs Richard Alpert to speak with a time-traveling John and tell him that he must bring everyone back to the island. After this, he goes to speak with Jacob. The season finale reveals that John Locke is still dead, and another entity has taken over his form, just to make Ben kill Jacob. In 1977, Juliet detonates the hydrogen bomb.

Season 6, the final, follows two timelines. In the first one, the survivors are sent to the present day, as the death of Jacob allows for his brother, the Man in Black, the human alter ego of the Smoke Monster, to take over the island. Having assumed the form of John Locke, the Smoke Monster seeks to escape the island and forces a final war between the forces of good and evil. The second timeline, called "flash-sideways" narrative, follows the lives of the main characters in a setting where Oceanic 815 never crashed though additional changes are revealed as other characters are shown living completely different lives than they did. In the final episodes, a flashback to the distant past shows the origins of the island's power and of the conflict between Jacob and the Man in Black, who are revealed to be twin brothers with Jacob desperate to keep his brother from leaving the island after he is transmogrified by the power of the island and becomes the smoke monster. The Man in Black seeks to kill all of the survivors, which were named "candidates" by Jacob and could become the new protector of the island. The ghost of Jacob appears to the last of the surviving candidates and Jack is appointed as the new protector. Jack catches up with The Man In Black, who says that he wants to go to the "center of the island" to turn it off, and therefore finally leave the island. They reach the place, but after doing this, The Man In Black becomes mortal. The Man In Black is killed by Jack, but Jack is seriously injured. Hurley, one of the survivors, becomes the new caretaker of the island. Several of the survivors die in the conflict or stay on the island, and the remaining escape in the Ajira Plane once and for all. Jack returns to the "center of the island" and turns it on again, saving it. Hurley, as the new protector, asks Ben to help him in his new job, which he agrees. After having saved the island, Jack dies peacefully in the same place in which he woke up when he arrived in the island. The series finale reveals that the flash-sideways timeline is actually a form of limbo in the afterlife, where some of the survivors and other characters from the island are reunited after having died. In the last scene, the survivors are all reunited in a church where they "move on" together.